Losartan improves renal function and pathology in obese ZSF-1 rats
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Zhi Su
Abstract
Background:
Losartan, a blocker of the angiotensin II type I receptor, is an important part of the standard of care for diabetic nephropathy (DN). The obese ZSF-1 rats display many aspects of the clinical features of human Type II DN. The current study was designed to examine the treatment effects of losartan on obese ZSF-1 rats and to evaluate the impact of the onset of dosing on efficacy.
Methods:
The rats (7–10 weeks) underwent a right uninephrectomy (Unx) or sham surgery. Losartan (3, 10, 30 mg/kg) was dosed 3 or 9 weeks post-Unx and continued for 12 weeks.
Results:
Treatment with losartan reduced urinary protein excretion and blood lipids (triglyceride and cholesterol) dose-dependently in both studies. The glomerular filtration rate (GFR) was significantly lower in obese ZSF-1 rats compared with those in lean rats, and losartan was efficacious against this endpoint, in particular with the earlier onset of treatment. Losartan also decreased tubulointerstitial fibrosis, and similar to GFR, earlier treatment conferred beneficial actions even at the lowest dose of 3 mg/kg. Several urinary biomarkers were elevated in the obese ZSF-1 rats, but the levels of sTNFR1, TIMP-1, L-FABP and KIM-1 were the only markers decreased by losartan.
Conclusions:
Losartan was renoprotective in the ZSF-1 rats with DN, improving both the pathological and functional parameters of the disease. Importantly, the data also highlight the importance of treatment at earlier stages of the disease for protecting against decline in the GFR and the development of fibrosis.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved its submission.
Disclosures: All authors are employees of AbbVie. The design, study conduct and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review and the approval of the publication.
Employment or leadership: Abbvie.
Honorarium: None declared.
References
1. Himmelfarb J, Tuttle KR. New therapies for diabetic kidney disease. New Eng J Med 2013;369:2549–50.10.1056/NEJMe1313104Search in Google Scholar
2. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013;382:260–72.10.1016/S0140-6736(13)60687-XSearch in Google Scholar PubMed
3. Packham DK, Alves TP, Dwyer JP, Atkins R, de Zeeuw D, Cooper M, et al. Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy: results from the DIAMETRIC (Diabetes mellitus Treatment for Renal Insufficiency Consortium) database. Am J Kidney Dis 2012;59:75–83.10.1053/j.ajkd.2011.09.017Search in Google Scholar PubMed
4. Fernandez-Fernandez B, Ortiz A, Gomez-Guerrero C, Egido J. Therapeutic approaches to diabetic nephropathy – beyond the RAS. Nat Rev Nephrol 2014;10:325–46.10.1038/nrneph.2014.74Search in Google Scholar PubMed
5. Waanders F, Visser FW, Gans RO. Current concepts of the management of diabetic nephropathy. Neth J Med 2013;71:448–58.Search in Google Scholar PubMed
6. Gosmanov AR, Wall BM, Gosmanova EO. Diagnosis and treatment of diabetic kidney disease. Am J Med Sci 2014;347:406–13.10.1097/MAJ.0000000000000185Search in Google Scholar PubMed
7. Tofovic SP, Kusaka H, Kost CK Jr, Bastacky S. Renal function and structure in diabetic, hypertensive, obese ZDFxSHHF-hybrid rats. Ren Fail 2000;22:387–406.10.1081/JDI-100100882Search in Google Scholar PubMed
8. Bilan VP, Salah EM, Bastacky S, Jones HB, Mayers RM, Zinker B, et al. Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF-1 rats. J Endocriol 2011;210:293–308.10.1530/JOE-11-0122Search in Google Scholar PubMed
9. Su Z, Widomski D, Ma J, Namovic M, Nikkel A, Leys L, et al. Longitudinal changes in measured glomerular filtration rate, renal fibrosis and biomarkers in a rat model of type 2 diabetic nephropathy. Am J Nephrol 2016;44:339–353.10.1159/000449324Search in Google Scholar PubMed PubMed Central
10. Zhang X, Jia Y, Jackson EK, Tofovic SP. 2-Methoxyestradiol and a-ethoxyestradiol retard the progression of renal disease in aged, obese, diabetic ZSF-1 rats. J Cardiovasc Pharmacol 2007;49:56–63.10.1097/FJC.0b013e31802cb88eSearch in Google Scholar PubMed
11. Rafikova O, Salah EM, Tofovic SP. Renal and metabolic effects of tempol in obese ZSF1 rats – distinct role for superoxide and hydrogen peroxide in diabetic renal injury. Metabolism 2007;57:1434–44.10.1016/j.metabol.2008.05.014Search in Google Scholar PubMed
12. Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, et al. SIRT3-AMP-activated protein kinase activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction. Circulation 2016;133:717–31.10.1161/CIRCULATIONAHA.115.018935Search in Google Scholar PubMed PubMed Central
13. Brenner BM, Cooper ME, De Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–9.10.1056/NEJMoa011161Search in Google Scholar PubMed
14. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;45:851–60.10.1056/NEJMoa011303Search in Google Scholar PubMed
15. Lee MY, Shim MS, Kim BH, Hong SW, Choi R, Lee EY, et al. Effects of spironolactone and losartan on diabetic nephropathy in a type 2 diabetic rat model. Diabetes Metab 2011;35:130–37.10.4093/dmj.2011.35.2.130Search in Google Scholar PubMed PubMed Central
16. Reddy MA, Sumanth P, Lanting L, Yuan H, Wang M, Mar D, et al. Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney Int 2014;85:362–73.10.1038/ki.2013.387Search in Google Scholar PubMed PubMed Central
17. Fan QL, Yang G, Liu XD, Ma JF, Feng JM, Jiang Y, et al. Effect of losartan on the glomerular protein expression profile of type 2 diabetic KKAy mice. J Nephrol 2013;26:517–26.10.5301/jn.5000176Search in Google Scholar PubMed
18. Schock-Kusch D, Xie Q, Shulhevich Y, Hesser J, Stsepankou D, Sadick M, et al. Transcutaneous assessment of renal function in conscious rats with a device for measuring FITC-sinistrin disappearance curves. Kidney Int 2011;79:1254–58.10.1038/ki.2011.31Search in Google Scholar PubMed
19. Dolber PC, Spach MS. Conventional and confocal fluorescence microscopy of collagen fibers in the heart. J Histochem and Cytochem 1993;41:465–9.10.1177/41.3.7679127Search in Google Scholar PubMed
20. Dubey R, Ghosh M. Simultaneous determination and pharmacokinetic study of losartan, losartan carboxylic acid, Ramipril, ramiprilate, and hydrochlorothiazide in rat plasma by a liquid chromatography/tandem mass spectrometry method. Sci Pharm 2015;83:107–24.10.3797/scipharm.1410-15Search in Google Scholar PubMed PubMed Central
21. Diogo LN, Faustino IV, Afonso RA, Pereira SA, Monteiro EC, Santos AI. Voluntary oral administration of losartan in rats. J Am Assoc Lab Anim Sci 2015;54:549–56.Search in Google Scholar PubMed
22. Roscioni SS, Heerspink HJ, de Zeeuw D. The effect of RAAS blockade on the progression of diabetic nephropathy. Nat Rev Nephrol 2014;10:77–87.10.1038/nrneph.2013.251Search in Google Scholar PubMed
23. Ziyadeh FN, Wolf G. Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rew 2004;4:39–45.10.2174/157339908783502370Search in Google Scholar PubMed
24. Jefferson JA, Shankland SJ, Pichler RH. Proteinuria in diabetic kidney disease: a mechanistic viewpoint. Kidney Int 2008;74:22–36.10.1038/ki.2008.128Search in Google Scholar PubMed
25. Cravedi P, Remuzzi G. Pathophysiology of proteinuria and its value as an outcome measure in chronic kidney disease. Br J Clin Pharmacol 2013;76:516–23.10.1111/bcp.12104Search in Google Scholar PubMed PubMed Central
26. Burnier M, Wuerzner G. Pharmacokinetic evaluation of losartan. Expert Opin Drug Metab Toxicol 2011;7:1744–7607.10.1517/17425255.2011.570333Search in Google Scholar PubMed
27. Titan SM, M Vieira J Jr, Dominguez WV, Barros RT, Zatz R. ACEI and ARB combination therapy in patients with macroalbuminuric diabetic nephropathy and low socioeconomic level: a double-blind randomized clinical trial. Clin Nephrol 2011;76:273–83.10.5414/CN107013Search in Google Scholar PubMed
28. Kowalski A, Krikorian A, Lerma EV. Diabetic nephropathy for the primary care provider: new understandings on early detection and treatment. The Ochsner J 2014;14:369–79.Search in Google Scholar
29. Mise K, Hoshino J, Ueno T, Hazue R, Sumida K, Hiramatsu R, et al. Clinical and pathological predictors of estimated GFR decline in patients with type 2 diabetes and overt proteinuric diabetic nephropathy. Diabetes Metab Res Rev 2015;31:572–81.10.1002/dmrr.2633Search in Google Scholar PubMed
30. An Y, Xu F, Le W, Ge Y, Zhou M, Chen H, et al. Renal histologic changes and the outcome in patients with diabetic nephropathy. Nephrol Dial Transplant 2015;30:257–66.10.1093/ndt/gfu250Search in Google Scholar PubMed
31. Jin HM, Pan Y. Angiotensin type-1 receptor blockade with losartan increases insulin sensitivity and improves glucose homeostasis in subjects with type 2 diabetes and nephropathy. Nephrol Dial Transplant 2007;22:1943–9.10.1093/ndt/gfm049Search in Google Scholar PubMed
32. Nishimura H, Sanaka T, Tanihata Y, Naito T, Higuchi C, Otsuka K. Losartan elevates the serum high-molecular weight-adiponectin isoform and concurrently improves insulin sensitivity in patients with impaired glucose metabolism. Hypertens Res 2008;31:1611–8.10.1291/hypres.31.1611Search in Google Scholar PubMed
33. Nakamura T, Fujiwara N, Sato E, Ueda Y, Sugaya T, Koide H. Renoprotective effects of various angiotensin II receptor blockers in patients with early-stage diabetic nephropathy. Kidney Blood Press Res 2010;33:213–20.10.1159/000316707Search in Google Scholar PubMed
34. Nielsen SE, Andersen S, Zdunek D, Hess G, Parving HH, Rossing P. Tubular markers do not predict the decline in glomerular filtration rate in type 1 diabetic patients with overt nephropathy. Kidney Int 2011;79:1113–8.10.1038/ki.2010.554Search in Google Scholar PubMed
35. Houlihan CA, Akdeniz A, Tsalamandris C, Cooper ME, Jerums G, Gilbert RE. Urinary transforming growth factor-beta excretion in patients with hypertension, type 2 diabetes, and elevated albumin excretion rate: effects of angiotensin receptor blockade and sodium restriction. Diabetes Care 2002;25:1072–7.10.2337/diacare.25.6.1072Search in Google Scholar PubMed
36. Agarwal R, Siva S, Dunn SR, Sharma K. Add-on angiotensin II receptor blockade lowers urinary transformin growth factor-beta levels. Am J Kidney Dis 2002;39:486–92.10.1053/ajkd.2002.31392Search in Google Scholar
37. Woo V, Ni LS, Hak D, Berard L, Zhu F, Khan S, et al. Effects of losartan on urinary secretion of extracellular matrix and their modulators in type 2 diabetes mellitus patients with microalbuminuria. Clin Invest Med 2006;29:365–72.Search in Google Scholar PubMed
38. Hostetter TH, Rosenberg ME, Ibrahim HN, Juknevicium I. Aldosterone in renal disease. Curr Opin Nephrol Hypertens 2001;10:105–10.10.1097/00041552-200101000-00016Search in Google Scholar PubMed
39. Epstein M. Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications. Am J Kidney Dis 2001;37:677–88.10.1016/S0272-6386(01)80115-3Search in Google Scholar PubMed
40. Kobori H, Mori H, Msaki T, Nishiyama A. Angiotensin II blockade and renal protection. Curr Pharm Des 2013;19:3033–42.10.2174/1381612811319170009Search in Google Scholar PubMed PubMed Central
©2018 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Review
- Calcium sensitization mechanisms in detrusor smooth muscles
- Opinion Paper
- The case for a distinctive philosophy of physiology and pathophysiology
- Behavior and Neuroprotection
- Effects of dizocilpine-induced glutamatergic blockade in the nucleus accumbens septi on the plus maze test
- Reproduction
- [6]-Gingerol modulates spermatotoxicity associated with ulcerative colitis and benzo[a]pyrene exposure in BALB/c mice
- Cardiovascular Function
- Blood troponin levels in acute cardiac events depends on space weather activity components (a correlative study)
- Effects of Trypanosoma brucei brucei infection and diminazene aceturate administration on the blood pressure, heart rate, and temperature of Wistar albino rats
- Oxidative Stress
- Dose-dependent effects of vitamin 1,25(OH)2D3 on oxidative stress and apoptosis
- Metabolism
- Losartan improves renal function and pathology in obese ZSF-1 rats
- Phytotherapy
- Evaluation of morning glory (Jacquemontia tamnifolia (L.) Griseb) leaves for antioxidant, antinociceptive, anticoagulant and cytotoxic activities
- Silymarin prevents lipid accumulation in the liver of rats with type 2 diabetes via sirtuin1 and SREBP-1c
Articles in the same Issue
- Frontmatter
- Review
- Calcium sensitization mechanisms in detrusor smooth muscles
- Opinion Paper
- The case for a distinctive philosophy of physiology and pathophysiology
- Behavior and Neuroprotection
- Effects of dizocilpine-induced glutamatergic blockade in the nucleus accumbens septi on the plus maze test
- Reproduction
- [6]-Gingerol modulates spermatotoxicity associated with ulcerative colitis and benzo[a]pyrene exposure in BALB/c mice
- Cardiovascular Function
- Blood troponin levels in acute cardiac events depends on space weather activity components (a correlative study)
- Effects of Trypanosoma brucei brucei infection and diminazene aceturate administration on the blood pressure, heart rate, and temperature of Wistar albino rats
- Oxidative Stress
- Dose-dependent effects of vitamin 1,25(OH)2D3 on oxidative stress and apoptosis
- Metabolism
- Losartan improves renal function and pathology in obese ZSF-1 rats
- Phytotherapy
- Evaluation of morning glory (Jacquemontia tamnifolia (L.) Griseb) leaves for antioxidant, antinociceptive, anticoagulant and cytotoxic activities
- Silymarin prevents lipid accumulation in the liver of rats with type 2 diabetes via sirtuin1 and SREBP-1c
